Hemophilia A results from absent or severely diminished levels of the procoagulant activity of factor VIII (VIII:C). Two additional activities related to F. VIII have been defined. These are Ristocetin cofactor or von Willebrand factor activity (VIIIR:WF) measured by the ability of F. VIII to aggregate human platelets in the presence of Ristocetin and a F. VIII-related antigen(s) (VIIIR:Ag) detected by heteroantisera to purified F. VIII. Unlike VIII:C, VIIIR:WF and VIIIR:Ag activity are generally normal in hemophilia A while all three activities are generally reduced in von Willebrand's disease (vWd). Whether molecular variants of hemophilia A exist in which inactive VIII:C molecules are present (CRM plus hemophilia A) or if there are other variants without an inactive protein (CRM minus hemophilia A) is in dispute. We will use a recently developed specific radioimmunoassay (RIA) for F. VIII coagulant related antigen (VIII:CRAg) utilizing alloantibodies to VIII:C. Unlike the VIIIR:Ag site detected by heteroantisera, VIII:CRAg is not detectable in most hemophilic plasmas. We will use the RIA for VIII:CRAg to characterize molecular variants of hemophilia A and study the mode of inheritance of these variants in hemophilia A kindred. The RIA for VIII:CRAg will be evaluated for its utility in carrier detection in hemophilia A.